Optimization of a privileged structure leading to potent and selective human melanocortin subtype-4 receptor ligands

Article abstract of DOI:10.1016/j.bmcl.2005.11.095

Design and synthesis of potent MC4 selective agonists based on cyclohexylpiperidine derived cyclic urea, oxazolidinones, and sulfonamide based privileged structures are disclosed.

Full text of DOI:10.1016/j.bmcl.2005.11.095

Bioorganic & Medicinal Chemistry Letters 16 (2006) 1130–1133
Optimization of a privileged structure leading to potent
and selective human melanocortin subtype-4 receptor ligands
Raman K. Bakshi,a,* Qingmei Hong,a Rui Tang,b Rubana N. Kalyani,b Tanya MacNeil,b
David H. Weinberg,b Lex H. T. Van der Ploeg,b Arthur A. Patchetta and Ravi P. Nargunda
aDepartment of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065-0900, USA
bDepartment of Obesity and Metabolic Research, Merck Research Laboratories, Rahway, NJ 07065-0900, USA
Received 7 November 2005; revised 25 November 2005; accepted 28 November 2005
Available online 20 December 2005
Abstract—Design and synthesis of potent MC4 selective agonists based on cyclohexylpiperidine derived cyclic urea, oxazolidinones,
and sulfonamide based privileged structures are disclosed.
Ó 2005 Elsevier Ltd. All rights reserved.
Melanocortin receptors are members of the family of
seven-transmembrane G-protein-coupled receptors.1
To date five different subtypes (MC1R–MC5R) have
been identified and cloned. Specifically, the melanocor-
tin-4 receptor (MC4R) is implicated in the regulation
of feeding behavior, energy homeostasis, and sexual dys-
function.1 Peptides melanocyte-stimulating hormone
(MSH) and adrenocorticotropic hormone (ACTH)
which are produced by cleavage of proopiomelanocortin
are the endogenous ligands for these receptors. The rela-
tionship of melanocortin with feeding behavior is very
well documented by the use of both non-selective pep-
tides and MC4R selective small molecules.2 Recently,
we reported the design of peptidomimetic MC4R li-
gands based on the privileged structure concept.3,4
These ligands mimic the His-Phe-Arg-Trp (HFRW)
pharmacophore found in MSH and cyclic peptide
MT-II.3 The peptidomimetic contains a dipeptide ad-
dress element 1 coupled to a privileged structure 2 that
incorporates both a hydrophobic group and polar resi-
dues. Previously, we disclosed selective MC4R ligands
3 and 4 which lower food intake and body weight in
rodents.3a,4 Additionally, these compounds were shown
also to augment erectile activity in rodents.3a,4
the heterocyclic and lipophilic structural features found
in MC4R ligands 3 and 4. Herein, we disclose our efforts
on the synthesis of newer analogs of generic structure 5
inspired by ligands 3 and 4.5
HN
H
H
N
N
OO
OH
N
Cl
N
N
Dipeptide Core
1
Privileged Structure
2
HN
H
H
N
N
O
O
NH2
OO
N
Cl
Cl
N
H
N
N
N
N
O
3
4
R
N
O
X = O or N
X
N
R = Dipeptide Core1
5
In order to gain further insights into this MC4R privi-
leged structure, we decided to identify a functional
mimetic of the highlighted substituents by combining
Our initial efforts were focused on optimization of the
five-membered heterocyclic ring of 5. The cyclic ureas
11 and 12 were probed initially and their synthesis was
accomplished as shown in Scheme 1. The aldehyde 7
critical to our need was obtained from the alcohol 6
Keywords: Privileged structure; Melanocortin-4.
*
Corresponding author. Tel.: +1 732 5946491; fax: +1 732 594
3007; e-mail: Raman_bakshi@merck.com
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.11.095

R. K. Bakshi et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1130–1133
1131
Preparation of the oxazolidinones 17a–f (Scheme 2)
also began with aldehyde 7. Reductive amination of
7 with appropriate aminoalcohols under the condi-
tions described for 8 furnished aminoalcohols 15a–f.
The aminols 15a–f on treatment with triphosgene in
the presence of DIEA furnished oxazolidinones 16a–
f. Removal of the Boc group gave the privileged
structures 17a–f. These were then fully elaborated to
compounds 19a–f using the chemistry described in
Scheme 1.
Boc
N
Boc
N
i
ii
OH
NH
CHO
7
6
Boc
N
Boc
N
iii
iv
O
NH
NBoc
N
8
9
Boc
N
H•HCl
Synthesis of cyclic sulfonamide analogs 24 and 25 were
deemed important targets to complete the SAR of the
privileged structure. Thus, amine 20 was obtained from
aldehyde 7 by catalytic reduction of the corresponding
oxime intermediate. The amine 20 was converted to
the sulfonamide 21 by reaction with 3-chloro-
propanesulfonyl chloride. Cyclization of 21 to 22 was
accomplished by treatment with NaH in DMF. Further
alkylation of 22 with methyl iodide resulted in the for-
mation of 23. Removal of the Boc group in 22 and 23
with HCl gave 24 and 25, which were transformed to
26 and 27 by following the chemistry described for
14a,b and 19a–f in Schemes 1 and 2.
N
O
N
v
O
N
N
N
10
11
H•HCl
Boc
N
N
O
O
N
v
NH
NH
N
12
9
NHBoc
O
Cl
N
vi
O
11 or 12
R
N
N
13a, R =H
13b, R =Me
Boc
Boc
N
N
i
ii
HN
H
N
OH
CHO
NH
R1 R2
OO
vii
Cl
N
15a, R1, R2 =H; 15b, R1 = Me, R2= Me;
7
O
R
N
15c, R1 = Me, R2 = H; 15d, R1 = H, R2 = Me;
15e, R1, R2 = CH2CH2; 15f, R1, R2 =CH2CH2CH2
N
14a, R =H
14b, R =Me
H•HCl
Boc
N
O
N
˚
Scheme 1. Reagents and conditions: (i) TPAP/NMO/CH2Cl2/4 A
molecular sieves; (ii) a—N-Boc-1,2-diaminoethane/toluene/AcOH/re-
flux using Dean–Stark; b—PtO2/H2/AcOH; (iii) NaH/THF/reflux; (iv)
NaH/MeI/THF; (v) HCl dioxane/CH2Cl2; (vi) N-Boc-D-(4-Cl)Phe/
EDC/HOBT/NMM/CH2Cl2; (vii) a—HCl/dioxane/CH2Cl2; b—N-
Boc-D-Tic/EDC/HOBT/NMM/CH2Cl2; c—HCl/dioxane/CH2Cl2.
iii
O
O
O
N
N
R1
R2
R1 R2
16a-f
17a-f
NHBoc
O
Cl
by TPAP oxidation.6 Reductive amination of aldehyde 7
with N-Boc-1-2-diaminoethane to afford 8 was accom-
plished first by forming the imine (azeotropic removal
of water by refluxing in toluene in the presence of a
catalytic amount of acetic acid). This was followed by
subsequent catalytic hydrogenation (PtO2) of the inter-
mediate imine in acetic acid. The amine 8 on reaction
with NaH in THF underwent cyclization to furnish
the cyclic urea 9, which was alkylated with methyl iodide
to furnish the N-methyl intermediate 10. Removal of
Boc protection in 9 and 10 with HCl furnished the
amines 11 and 12 as their hydrochloride salts. The inter-
mediates 11 and 12 were then coupled with N-Boc-D-(4-
Cl)Phe under EDC coupling conditions to give the
capped peptides 13a and 13b. Removal of Boc protec-
tion in 13a and 13b followed by EDC coupling with
N-Boc-Tic and subsequent Boc removal furnished 14a
and 14b.
N
v
iv
O
O
N
R2
R1
18a-f
HN
H
N
OO
Cl
N
O
O
N
R1
19a-f
R2
Scheme 2. Reagents and conditions: (i) a—aminoalcohol/toluene/
AcOH/reflux using Dean–Stark; b—PtO2/H2/AcOH; (ii) triphosgene/
DIEA/CH2Cl2/DMAP; (iii) HCl/dioxane/CH2Cl2; (iv) N-Boc-D-(4-
Cl)Phe/EDC/HOBT/NMM/CH2Cl2; (v) a—HCl/dioxane/CH2Cl2; b—
N-Boc-D-Tic/EDC/HOBT/NMM/CH2Cl2; c—HCl/dioxane/CH2Cl2.

1132
R. K. Bakshi et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1130–1133
Table 1. Binding affinity and selectivity for the human MCRa
Boc
Boc
N
b
N
Compound
IC50 (nM)
MC4R MC3R
1.2 0.11 761 31
4.8 2.6 520 120 150 25
i
ii
MC1BRc
MC5R
326 9
CHO
NH2
3
2063 73
1100 230
1800 10
2000 250
1100 150
1700 180
2400 910
2400 280
2100 250
7
14a
14b
19a
19b
19c
19d
19e
19f
26
20
4.3
4.0
2
2
660 38
460 75
160 28
180 15
Boc
N
Boc
N
iv
iii
Cl
0.8 0.31 230 48
1.3 0.12 210 10
80
110
7
3
N
NH
S
S
4.5 1.5
4.6 0.24 490
7.9 0.06 400 34
840 193 220 18
170 10
210
170 17
1200 180 0.62 0.13 760 350 190 30
O
O O
O
9
v
21
22
5
1300 260 0.91 0.25 310 64
H•HCl
N
Boc
N
27
30
v
1300 310
1100 60
2.1 0.89 380 52
8.1 630 72
200
630 41
9
33
2
N
R
N
S
a Values represent means standard error. All data represent at least
three determinations.
b Displacement of {125I}-NDP-a-MSH from human receptors expres-
S
R
O
O
O
O
24, R = H,
25, R =Me
23
sed in CHO cells.
c See Ref. 8.
HN
H
N
OO
Cl
vi
tional assays. In the oxazolidinone series analog 19b
with a geminal dimethyl group was at least 5-fold
more potent compared to the parent 19a in the bind-
ing assay. This was more or less true also for the
mono-substituted analog 19c (4R-methyl). The com-
plementary 4S-methyl analog (19d) was less potent
in comparison to 19c, suggestive of the fact that
there is some chiral recognition at the binding site.
Continuing forward the spiro-cyclopropyl and cyclo-
pentyl analogs 19e and 19f were as potent as oxazo-
lidinone 19a. The functional potencies for 19a–19f
were similar to binding potencies in that both 19c
and 19b were better than others in the series. Cyclic
sulfonamides 26 and 27 displayed the best potency
among the analogs we studied. Thus, they were 4-
fold more potent than the unsubstituted oxazolidi-
none 19a and cyclic ureas 14a and 14b in the MC4
binding assay (Table 1), but in the functional assay
(Table 2) oxazolidinone 19a and cyclic sulfonamides
N
N
R
R
S
O
O
26, R = H,
27, R =Me
Scheme 3. Reagents and conditions: (i) a—NH2OH/EtOH; b—PtO2/
H2/AcOH; (ii) 3-chloropropanesulfonyl chloride/CH2Cl2/pyridine; (iii)
NaH/DMF/80 °C; (iv) a—LDA/THF/À78 °C; b—MeI; (v) HCl/diox-
ane/CH2Cl2; (vi) as in Schemes 1 and 2.
The cyclic urea, oxazolidinone, and sulfonamide ana-
logs synthesized (Schemes 1–3) were evaluated for
MC4 activity in both the competitive binding assay
(Table 1) and functional assay (Table 2)7 as shown
below. Surprisingly, the cyclic urea analogs 14a and
14b were equipotent in both the binding and func-
Table 2. Functional potency and selectivity of compounds at the human melanocortin receptorsa
EC50 (nM) [% max]c
b
Compound
MC1BRd
MC4R
MC3R
MC5R
3
2850 450[95]
980 210[39]
950 180[43]
1300 190[56]
550 97[35]
2.1 0.2[97]
16 4.9[82]
16 3.5[88]
5.8 1.1[76]
2.4 0.5[82]
1.3 0.05[68]
8.6 1.6[90]
6.1 0.98[68]
15 1.1[65]
5.3 1.3[67]
5.8 1.4[74]
5.6 1.5[86]
14 1.8[95]
2487 43[32]
880 73[23]
1200 190[24]
[11]
737 65[61]
480 150[48]
460 15[63]
280 17[48]
340 12[38]
400 35[51]
400 23[53]
620 46[36]
1200 110[32]
660 85[41]
850 130[39]
800 100[48]
3600 930[51]
14a
14b
19a
19b
19c
19d
19e
19f
26
[6]
1300 240[40]
2100 690[72]
2600 110[48]
1700 200[25]
680 220[41]
460 260[27]
1500 340[39]
970 200[26]
370 57[15]
640 98[19]
990 82[15]
[6]
540 77[19]
450 21[18]
590 120[23]
550 68[37]
27
30
33
a Values represent means standard error. All data represent at least three determinations.
b Concentration of compound at 50% maximum cAMP accumulation.
c Percentage of cAMP accumulation at 10 lM compound relative to a-MSH.
d See Ref. 8.

R. K. Bakshi et al. / Bioorg. Med. Chem. Lett. 16 (2006) 1130–1133
1133
SAR of the oxazolidinone series led to the identifica-
tion of 4,4-dimethyl analog (19b) and 4R-methyl
group (19c) as potency enhancing motifs. Equally
interesting were the sulfonamides 26 and 27. Further
efforts are underway to expand on the scope of these
discoveries.
Boc
Boc
N
N
i
ii
NH2
NH
20
28
HN
H
N
H•HCl
N
OO
Cl
References and notes
N
O
iii
O
O
O
S
N
S
1. For recent reviews on melanocortin systems, see: (a) Chaki,
S.; Nakazato, A. Drugs Future 2004, 29, 1065; (b) Bedn-
arek, M. A.; Fong, T. M. Expert Opin. Ther. Patents 2004,
14, 1; (c) Catania, A.; Gatti, S.; Colombo, G.; Lipton, J. M.
Pharmacol. Rev. 2004, 56, 1; (d) Sebhat, I.; Ye, Z.;
Bednarek, M.; Weinberg, D.; Nargund, R.; Fong, T. M.
Annu. Rep. Med. Chem. 2003, 38, 31; (e) Gantz, I.; Fong, T.
M. Am. J. Physiol. Endocrinol. Metab. 2003, 284, E468; (f)
Speak, J. D.; Bishop, M. J. Expert Opin. Ther. Patents
2002, 12, 1613; (g) Wikberg, J. E. S. Expert Opin. Ther.
2001, 11, 61.
2. (a) Lu, D.; Willard, D.; Patel, I. R.; Kadwell, S.; Overton,
L.; Kost, T.; Luther, M.; Chen, W.; Woychik, R. P.;
Wilkison, W. O.; Cone, R. D. Nature 1994, 371, 799; (b)
Bultman, S. J.; Michaud, E. J.; Woychik, R. P. Cell 1992,
71, 1195; (c) Fan, W.; Boston, B. A.; Kesterson, R. A.;
Hruby, V. J.; Cone, R. D. Nature 1997, 385, 165.
3. (a) Sebhat, I. K.; Martin, W. J.; Zhixiong, Y.; Barakat,
K.; Mosley, R. T.; Johnston, D. B. R.; Bakshi, R. K.;
Palucki, B.; Weinberg, D. H.; MacNeil, T.; Kalyani, R.
N.; Tang, R.; Stearns, R. A.; Miller, R. R.; Tamvak-
opoulos, C.; Strack, A. M.; McGowan, E.; Cashen, D.
E.; Drisko, J. E.; Hom, G. J.; Howard, A. D.;
MacIntyre, D. E.; Ploeg, L. H. T.; Patchett, A. A.;
Nargund, R. P. J. Med. Chem. 2002, 45, 4589; (b)
Sebhat, I.; Zhixiong, Y.; Bednarek, M.; Weinberg, D.;
Nargund, R.; Fong, T. M. Annu. Rep. Med. Chem. 2003,
38, 31; (c) Patchett, A. A.; Nargund, R. Annu. Rep.
Med. Chem. 2000, 35, 289.
N
30
29
Boc
Boc
N
N
ii
iv
O
NH
N
O
N
28
31
Cl
HN
H
N
H•HCl
OO
N
iii
O
O
N
O
N
O
33
32
Scheme 4. Reagents and conditions: (i) acetone/CH2Cl2/AcOH/NaB-
H(OAc)3; (ii) a—CH2Cl2/CH3SO2Cl/DMAP/DIEA; b—CH2Cl2/diox-
ane/HCl; (iii) as in Schemes 1 and 2; (iv) CH2Cl2/EtOCOCl/DIEA/
DMAP.
26 and 27 had similar MC4 functional potency. This
suggests that 5-membered heterocycles are well toler-
ated in the binding assay, but there may be some
other elements which may also influence functional
potency. Furthermore, all analogs (across the series)
disclosed herein displayed significant selectivity for
MC4 receptors in both binding/functional assays
compared to other subtype receptors.
4. Bakshi, R. K.; Hong, Q.; Olson, J. T.; Ye, Z.; Sebhat, I. K.;
Weinberg, D. H.; MacNeil, T.; Kalyani, R. N.; Tang, R.;
Martin, W. J.; Strack, A.; McGowan, E.; Tamvakopoulos,
C.; Millar, R. R.; Stearns, E. A.; Tang, W.; Maclntyre, D.
E.; Ploeg, L. H. T.; Patchett, A. A.; Nargund, R. P. Bioorg.
Med. Chem. Lett. 2005, 15, 3430.
5. Part of this work was presented as a poster at 230th ACS
National Meeting, August 28–September 1, 2005, Wash-
ington, DC. Hong, Q.; Bakshi, R. K.; Tang, R.; Kalyani, R.
N.; Macneil, T.; Weinberg, D. H.; Ploeg, L. H. T.; Patchett,
A. A.; Nargund, R. Medi-82.
Further probing of the relationship between the substi-
tution on the heterocycle and the binding pocket in sul-
fonamide 26 and carbamate 19a led to the synthesis of
acyclic analogs 30 and 33. The synthesis of 30 and 33
was analogous to the chemistry described previously
and is shown in Scheme 4. Unfortunately, results from
the biology revealed that these compounds were less po-
tent than their corresponding cyclic analogs (Tables 1
and 2) and as a consequence were not pursued further.
6. Alcohol 6 was synthesized by following the chemistry
described in Ref. 3.
7. For detailed protocol of assay, see: (a) Bednarek, M. A.;
MacNeil, T.; Kalyani, R. N.; Tang, R.; Van der Ploeg, L.
H. T.; Weinberg, D. H. J. Med. Chem. 2001, 44, 3665.
8. Tan, C. P.; McKee, K. K.; Weinberg, D. H.; MacNeil, T.;
Palyha, O. C.; Feighner, S. D.; Hreniuk, D. L.; Van der
Ploeg, L. H. T.; MacNeil, D. J.; Howard, A. D. FEBS Lett.
1999, 451, 137.
In conclusion, design and the synthesis of potent and
selective MC4 agonists based on cyclic ureas, oxazo-
lidinones, and cyclic and acyclic sulfonamides privi-
leged structures are disclosed. A methodical study of